Lysergic acid amides

ABSTRACT

LYSERGIC ACID AMIDES OF THE FORMULA   4-R,7-(H3C-),9-(X-(CH2)N-CH(-Y)-NH-CO-),10,10A-DIDEHYDRO-   ERGOLINE   IN WHICH X IS HYDROXYL, THIOALKYL, PHENYL, HYDROXYL-SUBSTITUTED PHENYL, INDOLYL OR IMIDAZOLYL, Y IS HYDROGEN OR METHYLOL, N IS 1-3 AND R IS HYDROGEN OR METHYL, E.G. DLYSERGIC ACID - 2-AMIDO-HYDROXY-3-(4&#39;&#39;-HYDROXY-PHENYL)PROPANE, HAVE A SPECIFIC ANTISEROTONINE EFFECT AND ARE FREE OF OTHER EFFECTS ON THE CENTRAL AND VEGETATIVE NERVOUS SYSTEMS.

United States Patent 3,822,268 LYSERGIC ACID AMIDES Erzsbet Mag, neeKaracsony, Tibor Balogh, Jdzsef Borsi, Sandor Bajusz, Imre Moravcsik,Sandor Elek, Istvan Polgari, and Laszlo Lowinger, Budapest, Hungary,assignors to Kobanyai Gyogyszerarugyar No Drawing. Continuation-impartof abandoned application Ser. No. 721,860, Apr. 16, 1968. Thisapplication July 12, 1971, Ser. No. 161,975 Claims priority, applicationHungary, Apr. 20, 1967,

G0-1,012; Sept. 15, 1967, G01,028 Int. Cl. C07d 43/20 US. Cl. 260-2855 1Claim ABSTRACT OF THE DISCLOSURE Lysergic acid amides of the formula(CH2) -X OO-NH H N-CH:

in which X is hydroxyl, thioalkyl, phenyl, hydroxyl-substituted phenyl,indolyl or imidazolyl, Y is hydrogen or methylol, n is 1-3 and R ishydrogen or methyl, e.g. dlyserg c acid2-amido-1-hydroXy-3-(4'-hydroxy-phenyl)- propane, have a specificantiserotonine effect and are free of other effects on the central andvegetative nervous systems.

This is a continuation-in-part of our copending application Ser. No.721,860, filed Apr. 16, 1968 and now abandoned.

The invention relates to pharmacologically active new d-lysergic acidamides and their acid addition salts.

The amides of d-lysergic acid formed with aminoalcohols are ofconsiderable importance as pharmacologically N-CH wherein X is a memberselected from the group consisting of hydroxyl, thioalkyl, phenyl,hydroxyl-substituted 3,822,268 Patented July 2, 1974 phenyl, indolyl,and imidazolyl radicals, Y is a member selected from the groupconsisting of hydrogen and -'CH OH radicals, n is an integer from 1 to3, and R is selected from the group consisting of hydrogen and methylradicals.

The following compounds are preferable representatives of the compoundsof formula I:

d-lysergic acid-Z-amido-l-hydroxy-4-methylmercapto butane,

d-lysergic acid-2-amido-1-hydroxy-3-(4'-hydroxyphenyD-propane,

l-methyl-d-lysergic acid-Z-amido-1-hydroxy-3-(4'-hydroxy-phenyl-propane,

d-lysergic acid-l-amido-4-hydroxy-butane,

d-lysergic acid-Z-amido-1-hydroxy-3-phenyl-propane,

d-lysergic acid-2-amido-1-hydroxy-3-indolyl-propane,

and

d-lysergic acid-Z-amido-1-hydroxy-3-imidazolyl-propane.

The new compounds according to the invention can be prepared as follows:

The amide of lysergic acid formed with amino acid esters is prepared ina known way. Thereafter the ester group of the obtained lysergic acidpeptide ester is reduced with an alkaline earth metal borohydride to ahydroxymethyl group.

The d-lysergic acid amides used as starting material can be prepared bythe aid of known acylating processes, such as by acylating with lysergicacid chloride, lysergic acid mixed anhydride, lysergic acid azide oracylating in the presence of dehydrating agents. A preferable acylatingmethod is described in the British patent specification No. 480,822,which comprises the steps of preparing lysergic acid azide from lysergicacid hydrazide with a solution of sodium nitrite in a medium acidifiedwith hydrochloric acid, and after separation reacting the obtained azidein a solvent with a compound containing a primary amino group.

The lysergic acid peptide esters can be reduced with alkaline earthborohydrides preferably :by preparing the borohydride in situ, that is,by reacting an alkali metal borohydride, such as sodium or potassiumborohydride, with an alkaline earth metal salt, such as a halide, in thereaction mixture itself.

The reduction is preferably carried out in water, ethanol,tetrahydrofurane or diethylene glycol dimethylether as solvent.Consequently, it is convenient to carry out the reduction as follows.Adequate amounts of calcium chloride and sodium borohydride aredissolved in ethanol at a temperature of about 0 C.,- the solution iscooled to a temperature e.g. below -10 C., and an ethanolic solution ofthe lysergic acid peptide ester is added dropwise. After stirring for afew hours, reduction is complete. The course of the reaction can befollowed by a thin-layer chromatographic analysis on an aluminagypsumplate dried at C., developed with chloroform containing 2 percent ofethanol; the amide fluoresces in ultraviolet light. After completion ofthe reduction, the alkaline solution is acidified with an organic ormineral acid (e.g. hydrochloric acid, sulphuric acid, tartaric acid) topH 4-5, then the solution is evaporated to dryness. The residue isdissolved in water, the pH value of the solution is suitably adjustedand the product is extracted into a solvent (e.g. chloroform, ethylacetate, ethanol, isopropanol). After removing the solvent bydistillation, the crystalline product is isolated by filtration. Ifdesired, the acid-addition salt of the product can be prepared e.g. withan ethanolic solution of maleic acid, tartaric acid, ethanesulphonicacid or hydrochloric acid.

The new compounds according to the invention have primarily a specificantiserotonine effect and are free of other effects on the central andvegetative nervous systerns. Their antiserotomne effect is proved by thefact that in experiments carried out in vitro with various isolatedorgans, such as uterus of rat, and ileum of guinea pig, they inhibit inconcentrations of 10- to 10- g./ml. the contraction of unstriped musclesas produced by serotonine. In experiments carried out in viva theyspecifically inhibit in 50 to 250 rig/kg. intravenous doses thevasopressor efiect of serotonine on cats narcotised with Penthotal(sodium 5 ethyl-5-(l-methyl-butyl)-2-thiobarbiturate) and renderedhypotensive with a ganglionblocking agent. On rats they antagonise insubcutaneous doses of 15 to 100 rag/kg. the foot oedema produced withserotonine. Their eifect is specific against serotonine because they donot inhibit the effect of other vegetative pharmacons, such as acetylcholine, histamine, bradyquinine, kallikrein, vasopressine, adrenalin,nor-adrenalin, and isopropyl-nor-adrenalin, either on isolated organs orin in vivo experiments. Consequently, they do not show ananticholinergic, antihistaminic, quinine-antagonistic, aorp-adrenerg-blocking effect.

The new compounds according to the invention do not sow any neurotoxiceffect in animal tests. They do not cause changes in central nervoussystem stimulation and in the pathological behaviour on mice and rats insubcutaneous doses of 10 to 30 mg./kg. and in per os doses of 10 to 100mg./kg.

In electroencephalographic experiments as carried out on rabbits, theydo not induce an arousal reaction in intravenous doses of 0.1 and 1.0mg./kg., in contradistinction to the LSD, and they do not have anyfever-inducing effect.

On the basis of acute and chronic toxicological experiments carried outon various animals, such as rats, mice, rabbits and dogs, the compoundsproved to be only slightly toxic.

Due to their favourable biologic effect, the new compounds according tothe invention can be advantageously used for treating such diseaseswhere pathological vascular changes as induced by serotonine or theoverproduction of serotonine are the inducing pathological factor. Thus,they can be used as drug for preventing serious states of migraine, invarious angio-neurotic oedemas and in the state of vascular crisisesinduced by chromaphynomes.

The compounds according to the invention and their method of preparationare further illustrated by the aid of the following Examples.

EXAMPLE 1 Preparation of methyl2-(d-lysergamido)-4-methylmercapto-butyrate (a) Preparation of2-(d-lysergamido)-4-methylmercapto-butanoic acid methyl ester.1.46 g. ofmethyl Z-amino- 4-methylmercapto-butyrate are suspended in 50 ml ofethyl acetate. After adding 1.5 ml. of triethyl amine, the solution iscooled to C. and it is poured to the solution of 2.2 g. of d-lysergicacid azide in 100 ml. of ethyl acetate at a temperature of C. Thesolution is left to stand at 0 C. for a day, then it is evaporated. Theresidue is triturated with 20 ml. of water, then filtered, washedseveral times with water and dried.

(b) Preparation of 2-(d-lysergamido) 1 hydroxy-4- methylmercapto-butanemaleate-1.5 g. of methyl 2-(dlysergamido)-4-methylmercapto-butyrateprepared in step (a) are dissolved together with 1.5 g. of powderedcalcium chloride, under stirring, in 400 ml. of absolute ethanol. Thesolution is cooled to l0 C. in a salt-ice bath, then 0.8 g. of finelypowdered calcium borohydride is added, under further cooling andstirring. Reduction is complete at this temperature in 4 hours. Afterthe completion of the reduction process, the pH of the solution isadjusted with 5 N hydrochloric acid to 5, and the mixture is evaporatedto dryness in vacuo. The residue on evaporation is dissolved in 100 ml.of water, and the pH of the solution is adjusted to 8 with a 10 percentsolution of sodium hydroxide, then extracted by shaking with 8consecutive 50 ml. portions of a 4:1 mixture of chloroform andisopropanol. The combined organic phase is dried with anhydrous sodiumsulphate and evaporated to dryness. The dry residue is dissolved inethanol and maleic acid added to form the maleate of the title compound;m.p. 198-200 C.; [a] =-|-46.0 (c.=1, water).

EXAMPLE 2 Preparation of Z-(d-Iysergamido)-l-hydroxy-(4'-hydroxyphenyl)-propane (a) Preparation of methyl2-(d-lysergamido)-3-(4'-hydroxyphenyl)-propionate.-This compound isprepared from d-lysergic acid azide and 1.72 g. of methyl tyrosinatehydrochloride using the method of Example 1(a).

(b) Preparation of 2-(d-lysergamido)-1-hydroxy-3-(4'- hydroxy)-propanemaleate.26 g. of anhydrous calcium chloride are dissolved at 0 C. in 300ml. of absolute ethanol, then the solution is cooled to 10 C., and asolution of 1 g. of potassium borohydride in 15 ml. of ethanol is slowlyadded. To the suspension, the solution of the compound obtainedaccording to (a) in ml. of ethanol is added dropwise over about 2 hours,under continuous stirring. The product is isolated in the way specifiedin Example 2(a); mp. 161-163 C.; [a] =+27.78 (c.=1, water).

EXAMPLE 3 Preparation of 2-( l-methyl-d-lysergamido)-1-hydroxy-3-(4-hydroxyphenyl)-propane (a) Preparation of methyl 2-(l-methyl-d-lysergamido)- 3-(4-hydroxyphenyl)propionate.This compound isprepared from l-methyl-d-lysergic acid azide and 1.72 g. of methyltyrosinate hydrochloride, using the method of Example 1(a).

(b) Preparation of2-(l-methyl-d-lysergamido)-1-hydroxy-3-(4-hydroxyphenyl)-propane.Thecompound is prepared from the ester obtained under (a), using the methodspecified in Example 1(b) and employing 2.6 g. of anhydrous calciumchloride and 1.4 g. of sodium borohydride. The isomeric derivative isremoved from the product by chromatography on an alumina column,carrying out the elution with chloroform which contains 2 percent ofethanol. Melting point of the product: -117 C.; [a] =38.48 (c.=0.5,ethanol).

EXAMPLE 4 Preparation of 1-(d-lysergamido)-4-hydroxybutane (a)Preparation of methyl 1-(d-lysergamido)-butyrate-This compound isprepared from d-lysergic acid azide and 1.14 g. of methyll-amino-butyrate hydrochloride, using the method specified in Example1(a).

(b) Preparation of l-(d-lysergamido)-4-hydroxy-butane maleate-Thiscompound is prepared from the ester obtained under (a), using the methodspecified in Example 1(b). Melting point of the product: 177-179 C.;[a], =-+63.7 (c.=1, water).

EXAMPLE 5 Preparation of 2-(d-lysergamido)-l-hydroxy-3- phenyl-propane(a) Preparation of methyl 2-(d-lysergamido)-3-phenylpropionate.Thiscompound is prepared from d-lysergic acid azide and 1.6 g. of methyl2-amino-3-phenylpropionate hydrochloride, using the method described inExample 1(a).

(b) Preparation of 2 (d-lysergamido)-1-hydroxy-3- phenylpropanemaleate.The compound is prepared by reducing the ester obtained under(a), in the way specified in Example 1(b). The product is purified bychromatography on an alumina column, using chloroform as eluting agent.Melting point of the product: 201-203 C.; [a] 29.04 (c.=1, water).

5 EXAMPLE 6 Preparation of 2-(d-lysergamido)-1-hydroxy-3-indol-3'-yl-propane (a) Preparation of methyl 2-(d-1ysergamido)-3-indol-3-yl-propi0nate.-This compound is prepared from dlysergic acid azide and2.0 g. of methyl-2-amino-3-indol- 3-y1-propionate hydrochloride, usingthe method employed in Example 1(a).

(b) Preparation of 2-(d-lysergamido)-1-hydroxy-3- indol-3'-yl-propanemaleate.-'Ihis compound is prepared by reducing the ester obtained under(a) using the method employed in Example 1(b). The crude product ispurified by chromatography on an alumina column, using chloroform aseluting agent. [a] =+22.39 (c.=0.5, ethanol).

EXAMPLE 7 Preparation of 2-(d-1ysergamido)-1-hydroxy-3-imidazl-4'-y1-propane (a) Preparation of ethyl2(d-lysergarnido)-3-imidazol- 20 4-yl-propionate.This compound isprepared from dlysergic acid azide and 1.2 g. of methyl histidinate,using the method specified in Example 1(a).

(b) Preparation of 2-(d-lysergamido)-1-hydroxy-3- imidazo1-4'y1-propanetartrate.-This compound is prepared by the reduction of the esterobtained under (a),

employing the method specified in Example 1(b). The crude product ispurified by chromatography on an alumina column. The residue obtained byevaporating the chloroform eluate is dissolved in methanol and thetartrate prepared by adding tartaric acid. [04], -|-,65.1 (c.=0.5,percent aqueous ethanol).

What We claim is:

1. 2 (1 Methyl-d-lysergamido)-1-hydroxy-3-(4'-hydroxyphenyl) -propane.

References Cited UNITED STATES PATENTS 2,090,430 8/1937 Stoll et al.260-2855 2,997,470 8/1961 Pioch 260285.5 3,218,324 11/1965 Hofmann etal. 260-2855 3,346,580 10/1967 Hofmann et'al. 260--285.5

FOREIGN PATENTS 1,227,006 3/1971 Great Britain 260285.5

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

